Atypical parkinsonism caused by Pro105Leu mutation of prion protein: A broad clinical spectrum

Abstract

Objective: To delineate molecular and clinical characteristics of 3 families with PRNP P105L mutation, a variant of Gerstmann-Sträussler-Scheinker syndrome whose main motor symptoms were parkinsonism and/or involuntary movements.

Methods: The causative mutation was first determined in the affected patients of family 1 using whole-exome sequencing, and then mutational analysis was extended to families 2 and 3. The clinical features of the patients of these 3 families were summarized. Haplotype analysis was performed using high-density single nucleotide polymorphism array.

Results: The whole-exome sequencing revealed that the heterozygous mutation c.314C>T (p.P105L) in PRNP was the only known pathogenic mutation shared by the 3 patients of the family with autosomal dominant parkinsonism. We further identified the same mutation in patients of the other 2 families with autosomal dominant parkinsonism and/or involuntary movements. The clinical features of our patients with PRNP P105L mutation included various motor symptoms such as parkinsonism and involuntary movements in addition to progressive dementia. The clinical features in part overlapped with those of other forms of inherited prion diseases, such as fatal familial insomnia and Huntington disease-like type 1. The patients with PRNP P105L mutation shared a haplotype spanning 7.1 Mb around PRNP, raising the possibility that the mutations in the patients originated from a common founder.

Conclusion: Most of the patients presented with parkinsonism in addition to progressive dementia. Although spastic paraparesis has been emphasized as the main clinical feature, the clinical spectrum of patients with PRNP P105L is broader than expected.

Figure 1. Pedigree charts of 3 families with PRNP P105L

Affected individuals are indicated by filled symbols. Individuals whose DNA was available are indicated by stars. “P” indicates proband.

Figure 2. Identification of PRNP P105 and haplotype analysis of 3 families

(A) Identification of the causative mutation in PRNP. The upper panel shows the aligned short reads shown using Integrative Genomics Viewer. The lower panel shows the sequence data of direct nucleotide sequence analysis. (B) Haplotypes of 3 families. Haplotypes around a PRNP locus are shown. Single nucleotide polymorphisms (SNPs) in the blue-shaded area are the haplotypes containing the PRNP P105L mutation.

Figure 3. Prevalence of neurologic findings in 20 patients with PRNP P105

Neurologic findings of previously reported patients (10), our reported patients (9), and their family member (1). We summarized only members from whom we were able to obtain detailed neurologic findings. Black bars indicate previously reported patients. Gray bars indicate newly diagnosed patients. Seven patients had tremor, 4 of whom had postural tremor.